ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

In support of the message of this paper, we would like to report that mutations in ALDH18A1 , the causative gene in Coutelier’s paper, are the cause of SPG9 (MIM#601162), a rare form of autosomal dominant hereditary spastic paraplegia (HSP) complicated with vomiting and congenital bilateral cataracts that was reported by our group in a British family and an Italian family ( Slavotinek et al. , 1996 ; Seri et al. , 1999 ). The British family that we report presents one of the dominant mutations reported by Coutelier et al. (2015) . Furthermore, we show that the mutations we report here are loss-of-function mutations by using site-directed mutagenesis and enzyme activity studies with purified recombinant Δ 1 -pyrroline-5-carboxylate synthetase (P5CS), the enzyme encoded by ALDH18A1 . Finally, we provide some experimental and structural evidence that renders plausible a dominant negative mechanism for the dominant inheritance of the disease for these mutations and for other ALDH18A1 mutations exhibiting this type of inheritance.